Molecular Events in the PI3K/Akt Pathway in Thyroid Cancer

描述（申请人提供）：甲状腺癌是最常见的内分泌恶性肿瘤，近年来发病率迅速上升。需要为这种癌症制定更有效的管理策略，并需要更好地了解其分子机制。PI 3 K/Akt通路最近成为甲状腺癌分子紊乱的主要来源。特别是，在该通路内或与该通路相关的遗传和表观遗传改变及其关系，这在很大程度上尚未探索，是甲状腺癌发病机制中可以想象的关键分子事件。因此，我们提出了四个具体目标来检验我们的中心假设，即重要基因（例如，肿瘤抑制基因、甲状腺碘处理基因和癌基因）与由其遗传改变驱动的PI 3 K/Akt通路的相互作用是甲状腺癌发病的基本机制。在具体目标1中，我们将扩展我们最近发现的几个关键遗传改变，这些改变在未分化甲状腺癌中激活PI 3 K/Akt通路最有效，以在大量滤泡状和乳头状甲状腺癌中探索它们，以建立PI 3 K/Akt通路在甲状腺癌中的一般作用的遗传基础。类似于我们先前发现的与MAP激酶通路相关的异常基因甲基化，以及我们最近发现的甲状腺癌中某些基因甲基化与PI 3 K/Akt通路的相关性，我们将在特异性目的2中研究，PI 3 K/Akt通路的主要遗传改变与已知肿瘤抑制因子和甲状腺碘甲基化的关系-处理基因以及通过CpG甲基化微阵列分析揭示的与PI 3 K/Akt途径偶联的潜在的新的高甲基化肿瘤抑制基因和低甲基化癌基因。我们进一步假设，如果PI 3 K/Akt通路中的遗传和表观遗传改变或与之相关的遗传和表观遗传改变在甲状腺癌发病机制中很重要，则它们可能与甲状腺癌的临床病理结果较差相关。这将在特定目标3中通过检查这些遗传和表观遗传改变与甲状腺癌临床病理结果的相关性进行测试，这是一种可以揭示诊断和预后分子标志物的策略。我们最后假设，改变甲基化，因此，基因的表达，作为异常PI 3 K/Akt通路信号传导的结果，可能是可逆的，通过抑制这一途径，一种策略，可能具有重要的治疗潜力。这将在特异性目的4中通过功能性操纵PI 3 K/Akt信号传导并随后检查甲状腺癌细胞系中选定的功能重要基因的甲基化和表达的变化来进行测试。这是一个新的建议，第一次调查PI 3 K/Akt通路中的遗传和表观遗传分子事件及其作为甲状腺癌发病机制的基本分子机制的关系。由于拟定的策略侧重于选定的遗传和表观遗传改变，PI经验丰富的实验室配备了本项目最先进的专业知识和设备，预计拟定的研究将成功完成，这将对甲状腺癌发病机制的分子机制产生关键的见解，并发现新的诊断和预后分子标志物和治疗靶点，以改善甲状腺癌的发病机制。甲状腺癌的治疗方法

DESCRIPTION (provided by applicant): Thyroid cancer is the most common endocrine malignancy, with a rapidly rising incidence in recent years. Development of more effective management strategies for this cancer is needed and requires better understanding of its molecular mechanisms. The PI3K/Akt pathway has recently emerged as a major source of molecular derangements in thyroid cancer. In particular, genetic and epigenetic alterations within or linked to this pathway and their relationships, which have been largely unexplored, are conceivably critical molecular events in the pathogenesis of thyroid cancer. Consequently, we propose to pursue four Specific Aims to test our central hypothesis that coupling of altered methylation of important genes (e.g., tumor suppressor genes, thyroid iodide-handling genes, and oncogenes) to the PI3K/Akt pathway driven by its genetic alterations is a fundamental mechanism in thyroid cancer pathogenesis. In Specific Aim 1, we will extend our recent findings of several key genetic alterations that are most effective in activating the PI3K/Akt pathway in anaplastic thyroid cancer to explore them in a large set of follicular and papillary thyroid cancers to establish the genetic basis for a general role of the PI3K/Akt pathway in thyroid cancer. Analogous to our previous findings of aberrant gene methylation linked to the MAP kinase pathway and with our recent findings on the link of methylation of some genes to the PI3K/Akt pathway in thyroid cancer, we will investigate, in Specific Aim 2, the relationship of major genetic alterations in the PI3K/Akt pathway with methylation of known tumor suppressor and thyroid iodide-handling genes as well as potentially novel hypermethylated tumor suppressor genes and hypomethylated oncogenes coupled to the PI3K/Akt pathway that are revealed by CpG methylation microarray analysis. We further hypothesize that if the genetic and epigenetic alterations in, or linked to, the PI3K/Akt pathway are important in thyroid cancer pathogenesis, they are likely to be associated with poorer clinicopathological outcomes of thyroid cancer. This will be tested in Specific Aim 3 by examining the correlation of these genetic and epigenetic alterations with clinicopathological outcomes of thyroid cancer, a strategy that can reveal diagnostic and prognostic molecular markers. We finally hypothesize that altered methylation and, hence, expression of genes, as a consequence of aberrant PI3K/Akt pathway signaling, may be reversible by suppressing this pathway, a strategy that may have important therapeutic potential. This is to be tested in Specific Aim 4 by functionally manipulating the PI3K/Akt signaling and subsequently examining the change in methylation and expression of selected functionally important genes in thyroid cancer cell lines. This is a novel proposal that for the first time investigates both genetic and epigenetic molecular events in the PI3K/Akt pathway and their relationship as a fundamental molecular mechanism in thyroid cancer pathogenesis. With the proposed strategy to focus on selected genetic and epigenetic alterations and with the experienced laboratory of the PI that is equipped with state-of-the-art expertise and equipments for this project, successful completion of the proposed studies is expected, which should produce key insights into the molecular mechanisms of thyroid cancer pathogenesis and uncover novel diagnostic and prognostic molecular markers and therapeutic targets to improve the current management of patients with thyroid cancer.